Molecular glues that facilitate RAS binding to PI3Kα promote glucose uptake without insulin

  • Science. 2025 Jul 24;389(6758):402-408. doi: 10.1126/science.adr9097.
Koji Terayama  #  1 ,  Shinji Furuzono  #  1 ,  Nicole Fer  2 ,  Wupeng Yan  2 ,  Lucy C Young  3 ,  Daniel J Czyzyk  2 ,  Ruby Goldstein de Salazar  3 ,  Masato Sasaki  4 ,  Akihiro Uozumi  1 ,  Masahiro Konishi  1 ,  Shoichi Kanda  1 ,  Yoshitaka Sogawa  1 ,  Mitsuhiro Yamaguchi  5 ,  Takashi Tsuji  5 ,  Junichi Kuroyanagi  5 ,  Mayumi Hayashi  6 ,  Yuji Ogura  6 ,  Dhirendra K Simanshu  2 ,  Kazuishi Kubota  6 ,  Jun Tanaka  1 ,  Frank McCormick  2  3
Affiliations
  • 1. Cardiovascular Metabolic Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
  • 2. National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 3. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
  • 4. Organic and Biomolecular Chemistry Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
  • 5. Medicinal Chemistry Research Laboratory, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
  • 6. Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
  • # Contributed equally.
PMID: 40705882 DOI: 10.1126/science.adr9097
Abstract

While exploring strategies to control blood glucose concentrations in diabetes, we identified so-called Molecular Glues D223 and D927 that promote glucose uptake in the absence of Insulin. They act by increasing the binding affinity of phosphoinositide 3-kinase α (PI3Kα) catalytic subunit p110α to canonical small Guanosine triphosphatase Ras proteins and to RRAS, RRAS2, and MRAS by three orders of magnitude. The compounds bind to the RAS-binding domain of p110α, stabilizing the secondary structures of the PI3Kα in a RAS-binding conformation and forming direct interactions with Ras residues tyrosine-40 and arginine-41. In vivo, D927 mimicked the effects of insulin: It rapidly lowered blood glucose concentrations, enhanced Glucose Metabolism in normal and Zucker fatty rats, and improved hyperglycemia in models of type 1 and Type 2 Diabetes, even in insulin-deficient diabetic Animals.

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